Obesity has become a widespread health problem reaching an epidemic level in our society, with the affected individuals having a high risk for diabetes, heart disease, hypertension and cancer. The adipocyte- derived hormone leptin regulates energy balance by controlling food intake and metabolism. The leptin receptor long form (LepRb, or ObRb), which mediates important leptin responses, is highly expressed in hypothalamic nuclei known to regulate body weight and appetite. It has become clear that most obese individuals develop leptin resistance with dramatically increased plasma leptin levels. The lack of mechanistic understanding of leptin signaling has prevented us from designing effective therapeutic intervention of leptin resistance. It was proposed that inactivation of the tyrosine phosphatase Shp2 might overcome obesity and enhance leptin sensitivity, based on in vitro data showing a negative effect of Shp2 on the Jak2/Stat3 pathway. We have demonstrated recently, however, that mice deficient for Shp2 expression in forebrain neurons developed early-onset obesity and leptin resistance, but were not hyperphagic. Thus, we believe the novel obese mouse model created in this laboratory offers an unprecedented opportunity to delineate the neuronal control mechanism of energy homeostasis. We hypothesize that Shp2 acts to promote hypothalamic leptin signal flow and that enhancing the Shp2 phosphatase activity may improve leptin sensitivity. For this project, we will elucidate the physiological role of Shp2 in signaling events downstream of LepRb. We will also determine the concerted functions of Shp2 and StatS, two important players downstream of LepRb, in relay of hypothalamic leptin signals. Finally, we will determine whether selective expression of a dominant active Shp2 mutant in the hypothalamus potentiates leptin signals and alleviates diet-induced obesity in mice. A new paradigm will likely emerge from the proposed studies, which will illuminate the molecular signaling mechanism for leptin action in control of energy homeostasis.